A meta-analysis of four European genome screens (GIFT Consortium) shows evidence for a novel region on chromosome 17p11.2-q22 linked to type 2 diabetes

Abstract

Positional cloning is expected to identify novel susceptibility genes underlying complex traits, but replication of genome-wide linkage scan findings has proven erratic. To improve our ability to detect and prioritize chromosomal regions containing type 2 diabetes susceptibility genes, the GIFT consortium has implemented a meta-analysis of four scans conducted in European samples. These included the Botnia I and Botnia II scans, with respectively 58 and 353 pedigrees from Finland and Sweden, the Warren 2 scan performed in 573 multiplex sibships from the UK, and a scan of 143 families from France. The meta-analysis was implemented using the genome-search analysis method (GSMA), an exploratory data analysis technique which is robust across study designs. The analysis provided evidence for linkage of type 2 diabetes to six regions, with the strongest evidence on chromosome 17p11.2-q22 (P=0.0016), followed by 2p22.1-p13.2 (P=0.027), 1p13.1-q22 (P=0.028), 12q21.1-q24.12 (P=0.029), 6q21-q24.1 (P=0.033) and 16p12.3-q11.2 (P=0.033). Linkage analysis of the pooled raw genotype data generated maximum LOD scores in the same regions as identified by GSMA. Altogether, our results have indicated that GSMA is a valuable tool to identify chromosomal regions of interest and that accumulating evidence for linkage from small peaks detected across several samples may be more important than getting a high peak in a single sample. This meta-analysis has led to identification of a novel region on chromosome 17 linked to type 2 diabetes; this region has not been highlighted in any published scan to date but on the basis of these data justifies further exploration.